tbuckley/cabot-search huggingface dataset:
Primary care provider perceptions of patient participation in a multi-cancer early detection trial.
Authors: Ronald Myers, Mie Hallman, Kaitlyn Davis, Melissa DiCarlo, Constantine Daskalakis, Ayako Shimada, Botros Shenoda, Robert Danoff, Karen Dong, Christopher Chambers
Journal: Journal of Clinical Oncology (2023)

e13607 Background: Randomized clinical trials of multi-cancer early detection (MCED) tests are being planned, and primary care providers (PCPs) are likely to encounter patients who are considering participation. Little information has been reported about provider support for patient participation in such trials. Methods: We surveyed PCPs from 4 practices in a large health system to learn about their views on patient participation in a hypothetical MCED test trial. The PCPs received a link to view a patient-oriented infographic that described a trial in which participants would undergo serial blood draws for MCED testing and would be randomly assigned either to standard care or to receive MCED test results and follow-up, as needed. After viewing the infographic, respondents were asked to complete a brief survey that included statements related to factors that would affect their receptivity to patient participation in the trial, using a 5-point Likert type response scale that ranged from 1 = Strongly Disagree to 5 = Strongly Agree. The survey also included a single item that asked respondents if they would support patient participation in the trial and provided an opportunity to report the main reason for their answer. Finally, the survey contained a background characteristics section. We computed frequency distributions of survey responses. Results: Twenty-seven of 37 (73%) invited primary care providers completed the survey. About half of the respondents were women and two thirds were white; 81% were physicians while 19% were nurse practitioners, 54% were in practice for less than 20 years, all were board certified, and 74% had a hospital affiliation. Receptivity scores regarding a future MCED trial were high, with a mean of 3.8 and standard deviation of 0.6. Overall, 25 providers (93%) reported that they would support patient participation in an MCED test trial. The most commonly reported reasons for supporting patient participation were the belief that early cancer detection is important and the belief that research to develop new cancer screening tests is needed. The most commonly cited reasons for not supporting participation were concern about managing patients diagnosed with cancer in the trial and worry that trial participants would require too many practice resources. Conclusions: The overwhelming majority of respondents supported patient participation in an MCED test trial, but many were concerned about trial impact on their capacity to meet patient needs. Further research is needed in a larger study to validate these results and learn more about factors likely to influence PCP support for patient participation in MCED test trials and actual participation.
A phase 1B dose escalation study of ETC-159 in combination with pembrolizumab in advanced or metastatic solid tumours.
Authors: David Shao Peng Tan, Matthew C.H. Ng, Vivek Subbiah, Wells A. Messersmith, John H Strickler, veronica diermayr, Julienne Cometa, Stephanie Blanchard, Ranjani Nellore, Vishal Pendharkar, Bong Hwa Gan, Nurul Nazihah Rozaini, Claudia Koh, Suman Sarma, Huay Mei Poh, Alexander Lezhava, VENKATESHAN SRIRANGAM PRATIVADIBHAYANKARAM
Journal: Journal of Clinical Oncology (2023)

2601 Background: ETC-159 is a small molecule porcupine inhibitor, in a prior Phase 1 study was safe as a monotherapy at 16 mg or at 24 mg with the addition of preventive denosumab for bone protection. In this Ph1B open-label trial the safety, MTD, PK and pharmacodynamics (PD) of ETC-159 in combination with pembrolizumab were determined (NCT02521844). Methods: Eligible patients had adequate organ function, advanced or metastatic solid malignancies and had failed standard treatments. Patients’ refractory/resistant to prior PD-1 treatment were allowed and all patients had to have serum β-CTX levels below 600 pg/mL (or &lt;1000 pg/mL and preventive denosumab). Dose escalation followed a 3+3 design with a DLT period of 42 days. ETC-159 was dosed orally QOD in 21-day cycles (8-24 mg); pembrolizumab was dosed IV at 200 mg Q3W. Day 1 and trough PK were determined for ETC-159 and pembrolizumab. Responses were assessed every 6 weeks (RECIST 1.1). Results: 20 patients were enrolled, 6 in the 8 mg cohort and 14 in the 16 mg cohort (50% M and 50% F, mean age of 51.4 y). All patients have been discontinued: 16 due to disease progression; 1 due to AEs, 2 developed contra-indication to denosumab &amp; pembrolizumab, 1 withdrawal of consent. PK parameters of ETC-159 in the first cycle were consistent with prior single agent data. TEAEs were reported in all subjects in the study with most events being grade 1/2, with dysgeusia (65%), β-CTX increase (30%), fatigue (25%), constipation (20%), and nausea (20%) being the most common. DLTs were G3 colitis and G3 immune-related enteritis (16 mg, 2 patients), and pneumonitis and erythema with fever (8 mg, 1 patient). Other drug related SAEs were G2 thyroiditis, hematuria, and thrombocytopenia. No fractures or other drug related skeletal SAEs. Of the 15 evaluable patients, 6 (40%) demonstrated clinical benefit (1 PR, 5 SDs) in combination with pembrolizumab (2 ovarian, 1 lung, 1 pancreatic, 1 urachal, 1 MSS CRC patient with RSPO fusion), at the first assessment, in a predominantly MSS population (65% MSS, 25% unknown, 10% MSI). Pharmacodynamics, (hair follicle Axin2 reduction), was detected at both dose levels and was ≥80% from baseline on D15. Conclusions: ETC-159 + pembrolizumab was well tolerated; 8 mg of ETC-159 in combination with pembrolizumab was determined to be the MTD/RD. Preliminary data suggest Wnt signaling inhibition in combination with checkpoint inhibition may provide clinical benefit in MSS patients. Clinical trial information: NCT02521844 .
Clinical and immune phenotypes associated with immune checkpoint inhibitor-induced autoimmune diabetes.
Authors: Karina Nicole Ruiz-Esteves, Kaitlyn Shank, Tianqi Ouyang, Caitlin Colling, Leyre Zubiri, Alexandra-Chloé Villani, Kerry Lynn Reynolds, Michelle Rengarajan
Journal: Journal of Clinical Oncology (2023)

2509 Background: ICI-induced autoimmune diabetes (ICI-DM) is an immune-related adverse event (IrAE) that affects approximately 1% of patients who receive ICI. Most reports of ICI-DM suggest that it resembles fulminant type 1 diabetes, with low or absent endogenous insulin production at presentation. However, milder cases have recently been reported, suggesting a more heterogeneous disease. In this study, we identified distinct clinical phenotypes of ICI-DM that may improve individualized approaches to management. Methods: We performed a retrospective chart review of 16,582 patients treated with either anti-PD1, anti- PDL1, anti-CTLA4, or combination between 2010 and 2022 in a multi-centered academic hospital system. We identified patients with ICI-DM as those with a new diagnosis of type 1 diabetes or drug-induced diabetes and a prescription for medium- or long-acting insulin following ICI therapy; cases were confirmed by chart review by two board-certified endocrinologists. To phenotype ICI-DM based on endogenous insulin production, we reviewed all patients with ICI-DM who had a C-peptide level in our system, which allowed us to identify and subdivide 57 cases of ICI-DM. These patients were further characterized at both initial presentation and up to 30 months of follow-up. Results: We identified six distinct groups of ICI-DM based on the presence (A+) or absence (A-) of diabetes-specific autoantibodies, further divided by level of endogenous insulin production, preserved (B+), low (B+/-) or undetectable (B-). In our cohort, A+B- patients showed to have the lowest time to diagnosis (median 45 days) and high rates of both DKA and hospitalization (67%) at presentation. At the other end of the spectrum, A-B+ patients had a longer time to diagnosis (median 176 days) and no evidence of DKA or hospitalization at presentation. Surprisingly, all groups had similar insulin requirements without significant dosage variations at 30-month follow up. Elevated lipase levels varied widely across groups with the highest rate (66.7%) reported in the A+B- cohort. The prevalence of thyroiditis in our cohort was highest in the A-B- group but did not seem to follow any specific distribution. Conclusions: Our study examined the largest data set to date of deep clinical phenotyping of patients with ICI-DM. We define at least three distinct subsets of ICI-DM, with A+B- patients being most similar to the initially described cases of fulminant type 1 diabetes. Patients with negative antibodies seem to have a milder form of the disease. Our findings also suggest significant heterogeneity and distinct underlying mechanisms amongst cases of ICI-DM. Further studies will be needed to elucidate whether these findings could extrapolate to other individual IrAEs, which may also encompass distinct phenotypes with distinct mechanisms.
A novel method that leverages existing data to conduct comparative analyses of competing assets: Sugemalimab and agents targeting the PD-L1/PD-1 axis as an example.
Authors: Antonio Tito Fojo, Mengxi Zhou, Meredith LaRose, Susan Elaine Bates, Lawrence Howard Schwartz
Journal: Journal of Clinical Oncology (2023)

2609 Background: Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. Numerous immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) axis have garnered regulatory approvals. A novel method of comparative analysis that discerns differences/similarities amongst such agents could reduce redundancy and hopefully enhance true competition. Methods: We’ve described an approach for assessing efficacy that assumes changes in tumor quantity result from two simultaneous processes – exponential decay of the treatment-sensitive fraction of tumor at rate d, and exponential growth of the resistant fraction at rate g. Using this method, the USFDA analyzed data from 9934 patients with NSCLC enrolled in registration trials treated with chemotherapy, targeted therapies, and immunotherapies concluding g is inversely associated with survival across treatment types and encouraging prospective studies to evaluate whether g derived from early tumor measurements might serve as an earlier clinical trial endpoint (Gong ASCO 2020). Using data provided by EQRx and CStone we analyzed the GEMSTONE-302 trial comparing chemotherapy +/- the PD-L1 inhibitor sugemalimab in first line NSCLC. Results: 88% of the data could be analyzed. Regression without growth was seen in 10-12% of both arms with indistinguishable d values. Evidence of tumor growth was estimable as a g value in 68-71% with statistically slower g values and longer tumor doubling times (TDT) seen with sugemalimab + chemotherapy [0.0012/day (0.0005-0.0022); TDT 578d] than placebo + chemotherapy [0.0025/day (0.0013-0.0035); TDT 277d] p&lt;0.0001. A comparative analysis with FDA data from 1521 patients who received Combo ICI in front line, finds comparable/slightly slower g values for sugemalimab + chemotherapy using all or a fraction of the data. Conclusions: We used a method of analysis that estimates rates of tumor growth ( g) to analyze the efficacy of the PD-L1 antagonist, sugemalimab, in NSCLC. Because time is included in our equations the intervals of assessment are rendered inconsequential, making this method of analysis ideal for virtual comparisons. We confirmed the value of sugemalimab in the first-line setting by demonstrating its data track very closely with data aggregated from randomized trials reported by the USFDA in patients treated with Combo ICI in front line. Because g values can be estimated with fewer data it can be leveraged for early decisions. [Table: see text]
Pan tumor outcomes to immune checkpoint inhibitors in patients of Native American origin in the United States: The multicenter POINT-US study.
Authors: Minh Duc Phan, Paul Antoine El Tomb, Tariq Khreis, Tobias Meissner, Rachel Elsey, Bing Xu, Junaid Arshad, Umbreen Arshad Rozell, Elysia Tjong, Vaia Florou, Sonam Puri, Arsalan Khan, Dorothy Rhoades, Raid Aljumaily, Adanma Ayanambakkam, Anthony Burtman, Mark Bigbey, Michael Sjoquist, Casey B. Williams, Abdul Rafeh Naqash
Journal: Journal of Clinical Oncology (2023)

2654 Background: Despite receiving identical standard-of-care therapies, epidemiological data indicate that Native American (NA) patients (pts) with cancer have worse outcomes vs. White pts. ICIs have revolutionized the treatment of certain tumors, however pts from certain racial and ethnic groups, including NA pts, are underrepresented in ICI trials. Methods: This is an ongoing multi-center retrospective study across four U.S. academic cancer centers that serve a high volume of NA pts. We included pts with self-reported race as NA in electronic medical records. We evaluated clinical outcomes and immune-related adverse events (irAEs) of 71 NA pts age ≥18 years with various solid tumors treated with ICI-based therapies between 2015 to 2021. IrAEs were defined based on the Common Terminology Criteria for Adverse Events (version 5.0) or RECIST 1.1. as available, was used to determine objective response rate (ORR). Kaplan Meier log-rank method was used to generate median progression free survival (mPFS) and median overall survival (mOS). Results: Median age (range) at ICI initiation was 62 (24 -81) years; 43 (60%) were males, with 26 (37%) females, 2 pts with missing gender data. 55 (77%) of pts had ECOG performance status 0. The distribution of top six tumor types included (number of pts [%]): non-small cell lung cancer (NSCLC) 22 (31%), renal cell carcinoma (RCC) 16 (23%), melanoma 7 (10%), small cell lung cancer (SCLC) 4 (6%), hepatocellular carcinoma 4(6%); colorectal adenocarcinoma, head and neck squamous cell carcinoma, cervical squamous cell carcinoma each had 3 pts (4%). Most pts (51 [72%]) received single agent ICI, 12 (17%) had dual ICI, 4 (6%) had chemotherapy+ ICI, and remaining had either ICI + tyrosine kinase inhibitor or ICI + study drug (4 [6%]). 55% of pts with NSCLC underwent tumor next-generation sequencing (NGS) while &lt;30% of patients with renal cell carcinoma or melanoma had tumor NGS performed. Among 71 pts, 17 (24%) had any grade (G) irAE, 4 (6%) were reported to be ≥G3. The median time to irAE onset was 18 weeks and 3 (4%) pts discontinued ICI due to irAEs. The mPFS, mOS and ORR for the most frequent tumors (N ≥5) are shown. Conclusions: Although limited by sample size, our emerging data provides new insights into ICI efficacy and irAEs in NA pts that have been unknown to date. To our knowledge, this is the first and only attempt to date evaluating ICI outcomes in NA pts. Updated clinical data and tumor genomics will be presented at the meeting. [Table: see text]
High transferrin receptor expression marks tumors with increased immune-effector infiltration and expression of targetable checkpoint molecules: Results of a multi-cancer analysis in solid tumors.
Authors: Asaad Trabolsi, Artavazd Arumov, Nishant Gandhi, Alex Patrick Farrell, Irene Kang, Dave S. B. Hoon, Sam Wei, Milan Radovich, George W. Sledge, Stephen V. Liu, Patrick C. Ma, Jonathan Harry Schatz
Journal: Journal of Clinical Oncology (2023)

2613 Background: The cell-surface transferrin receptor, TFR1, encoded by TFRC, imports iron-bound transferrin into cells to drive tumor proliferation. We have found worse prognosis with high TFRC expression across multiple tumor types. The mechanism by which TFRC drives tumor cell- intrinsic oncogenesis is multifactorial, but its interaction with the tumor microenvironment (TME) has not been studied. Here, we assessed TME infiltration by immune effector populations and immune checkpoint expression. Methods: Tissue samples underwent comprehensive molecular profiling at Caris Life Sciences: Next-gen sequencing of DNA (592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq), RNA- seq (NovaSeq, whole transcriptome sequencing, WTS) and immunohistochemistry. RNA deconvolution analysis by the Microenvironment Cell Populations (MCP)-counter method quantified immune populations to assess T cells, B cells, natural killer cells (NK) and myeloid dendritic cells (MDC). Analyses compared quartiles of TFRC mRNA expression between Q4 ( TFRC-H) high and Q1 ( TFRC-L) low expressors. Results: Among 27,607 patients with non-small cell lung cancer (NSCLC), 5,332 with prostate cancer (PC), and 14,287 with colorectal cancer (CRC), TFRC-H tumors were associated with high tumor mutational burden (TMB-high, ≥10 mutations/MB), and TP53 mutation (q&lt;0.05). Multiple immune checkpoint genes showed significantly higher expression in TFRC-H relative to TFRC-L in all tumor types, including CD274 (PDL1), LAG3, PDCD1LG2 (PDL2), and CTLA4 (Table; All values are statistically significant: q&lt;0.05). Moreover, TME assessment by MCP-counter showed significantly increased infiltration by total T cells, CD8+ cells, B cells, NK cells, and MDCs in TFRC-H (Table). Finally, among patients who received Check-point inhibitors (CPI), TFRC-L had improved survival (HR=0.807 (95% CI 0.76 – 0.85) p&lt;0.00001) in NSCLC but no difference was found in CRC or PC. Conclusions: Our study is the first to reveal the TME characteristics associated with TFRC expression in a variety of solid tumor types. We found TFRC-H tumors have increased infiltration by immune effector populations but also express significantly higher levels of immune checkpoint molecules, highlighting immune exhaustion. Altered iron metabolism has been shown to promote tumorigenesis and here we identify a new role for TFRC in remodeling the TME. TFR1- targeting therapeutic agents are in clinical development and warrant further investigation in combination with CPIs. [Table: see text]
Accrual of adolescents and young adults (AYA) into cancer clinical trials in Canada.
Authors: Mariam Jafri, Corey Willman, Alison May Urton, Jan-Willem Henning, Lesleigh S. Abbott, Kelly Davison, Mohamed A. Akra, Lesley Seymour, Janet Ellen Dancey, Annette E. Hay
Journal: Journal of Clinical Oncology (2023)

e13598 Background: Historically, accrual rates of AYA (aged 16-39) to cancer clinical trials have been low. This is suggested to contribute to lesser improvements in their outcomes compared with older and younger populations. We sought to describe the impact of collaborative initiatives launched by the Canadian Cancer Trials Group (CCTG), NCTN and C17 to address this. Methods: All CCTG trials open to accrual from 01/01/2004 to 31/12/2022 were evaluated. Trials with eligibility criteria limited to age &gt; 39, or for which CCTG did not have access to individual patient data on age, were excluded. Accrual rates were assessed by age (&lt;30, 30-39, &gt;40 yrs), cancer type, and compared with 2022 Canadian Cancer Society (CCS) prevalence data. Results: 379 studies were open to accrual. 21 trials were excluded as they had no patients aged 16-39 within their inclusion criteria. 2 trials were excluded as they were either COVID related or a trial sub-study. 230 trials were excluded owing to patient age data being unavailable to CCTG. 126 CCTG and NCTN led trials were included. They involved the following disease sites: brain (3), breast (13), GI (12), GU (11), gynecology (6), head &amp; neck (3), hematology (10), lung (11), melanoma (4), sarcoma (2) novel investigational agents (45) and symptom control (6) – the latter two spanned multiple tumor types. Patients aged 16-18 were excluded from many trials limiting accrual opportunities in this subgroup. AYA patients were recruited into trials at a higher level than expected by prevalence data except for brain, lung and head &amp; neck patients. This may be due to younger, fitter patients being recruited onto trials. GU trials, hematology and sarcoma trials recruited better than expected as there were trials geared to diseases common in younger individuals (e.g. germ cell cancers) and incorporating intensive therapy e.g. stem cell transplantation in lymphoma. 3.5% of patients accrued on trials were &lt;40 in 2004-2013 c.f. 8.7% of patients 2014-2022. Conclusions: Limited data is available on AYA aged 16-18 due to trial entry criteria. Currently, most CCTG trials include patients aged ≥14. Trial accrual in the AYA population was higher than predicted by CCS data indicating that clinical trials are acceptable to AYA patients. This supports ongoing efforts to improve trial access to AYA. [Table: see text]
A phase Ia trial to evaluate the safety and efficacy of HB0030, an anti-TIGIT antibody, in patients with advanced solid tumors: Preliminary results.
Authors: Huan Zhou, Wei Li, Jing Xie, Hongtao Li, Xiangyang Zhu, Yongmin Yang, Yang Yang, Yang Zheng, Qiaofeng Wang, Juan Chen, Chao Li, Ruirui Xu, Jingjing Wang, Yiran He
Journal: Journal of Clinical Oncology (2023)

e14673 Background: HB0030 is an IgG1 type humanized monoclonalanti-TIGIT antibody. Its heavy chain Fc fragment is wild-type that preserves function for inducting CDC and ADCC effects. Nonclinical data showed that HB0030 has a good affinity for TIGIT and anti-tumor activity. Methods: This is an ongoing single-center, open-label, dose escalation Phase Ia study to mainly evaluate HB0030 safety, antitumor activity and immunogenicity in patients (pts) with advanced solid tumor. HB0030 is administered by IV infusion every 21 days. An accelerated titration method combined the standard 3+3 design was utilized for dose escalation, which of contained 8 dose groups (0.1, 0.3, 1.0, 3.0, 10, 20, 30, 40mg/kg). The tumor assessment evaluated by investigator according to RECIST v1.1. Results: As of Jan 9, 2023, 20 pts (4Male/16Female) with advanced malignant solid tumor have been enrolled and dosed at 0.1mg/kg (n = 1), 0.3mg/kg (n = 3), 1mg/kg (n = 3), 3mg/kg (n = 4), 10mg/kg (n = 3) and 20mg/kg (n = 6). The median age was 56.9 years. All pts had stage IV disease and failed from the anti-tumor standard therapy with a median of 3 lines. The main tumor types included lung(n = 6), breast(n = 3), colorectal(n = 3) and cervical (n = 2) cancer. Total 16 pts have completed at least once tumor assessment. The ORR and DCR were 6.3% (1/16) and 62.5% (10/16), respectively. The best response was a PR with 47% tumor regression pt who was diagnosed non-small cell lung cancer (NSCLC) accompanied with TP53 gene mutation. The pt relapsed with multiple metastasis after radical operation and adjuvant chemotherapy, and failed to systemic chemotherapy combined targeting anti-vascular therapy. He achieved PR with 3 cycles of 20mg/kg HB0030 treatment, and PR status continued at present. A NSCLC pt maintained 24 weeks SD after 3mg/kg HB0030 administration. The most common treatment related adverse events (TRAEs) were lymphopenia (9/20, 45%) and shortened activated partial thromboplastin time (APTT) (6/20,30%). Grade 3 TRAEs occurred in 15% of pts (3/20) which included thrombocytopenia, anemia, syncope and hypertension. There were no Grade 4-5 AEs, serious adverse events (SAEs), dose-limiting toxicity (DLT) and death. The anti-drug antibodies (ADAs) were detected in 2 pts in 20 mg/kg dose group, and not caused by HB0030 therapy because it had existed in baseline. Conclusions: HB0030 showed very well safety in the stage of dose escalation from 0.1 to 20 mg/kg, and potential promising anti-tumor activity above 3mg/kg dose in advanced solid tumors pts, especially in NSCLC. Currently, 30mg/kg and 40mg/kg dose escalation are ongoing. Clinical trial information: NCT05706207 .